Epilepsy Pathology PDF

Epilepsy Pathology Epilepsy: chronic disease characterized by recurrent, unprovoked seizures DX: at least 2 unprovoked seizures occurring more than 24 hrs apart Seizure: abnormal excessive cerebral neuronal discharge with or without a change in level of consciousness Convu...

Epilepsy Pathology Epilepsy: chronic disease characterized by recurrent, unprovoked seizures DX: at least 2 unprovoked seizures occurring more than 24 hrs apart Seizure: abnormal excessive cerebral neuronal discharge with or without a change in level of consciousness Convulsion: abnormal,involuntary muscle contraction sen with certain seizure disorders prodrome: symptoms hours or days before a seizure Aura: beginning of seizure - seconds to minutes before ictus: actual seizure, time from first symptom to end interictal: period between seizures. May include deep sleep, HA, vomiting, confusion, more than 99% of their life medical marijuana often has a clinical benefit Causes ○ 70% idiopathic (primary) ○ 11% CVD ○ 5% developmental ○ 4% head injury Pathophysiology ○ Glutamate = excitation ○ GABA = inhibition ○ alteration of these can lead to seizures ○ Seizure EEG: brain discharge MUCH different, physiological change in the brain ○ most seizures start in small groups of injured, hyper-excitable neurons (foci) ○ U shaped curve of who is affected - predominately young children and older adults ILAE Classification of Seizures ○ FOCAL SEIZURES (partial) - affects only one part of the brain. Can turn into generalized. CLASSIFIED ON CONSCIOUSNESS simple focal patient retains consciousness small region of the brain only may have motor involvement simple activities 15 sec-3 min complex focal blank stare begin as simple focal may include an aura patient consciousness impaired secondarily generalized Consciousness impaired ○ GENERALIZED SEIZURES - involve entire brain. Loss of consciousness tonic-clonic  muscle stiffening, tongue biting, urinary incontinence, absence of breathing GRAND MAL 30-60 seconds absence myclonic tonic atonic Epilepsies and Epilepsy Syndrome Epilepsy diagnosis ○ Observation ○ neurological examination ○ neuropsychological tests ○ blood tests ○ EEG multiple electrode cap alpha waves awake but quiet beta waves awake, attentive theta waves sleep, emotional stress some disorders delta waves deep sleep severe disorder ○ brain imaging CT scan MRI regular functional PET scan SPECT scanner Epilepsy Therapy ○ GOAL: no seizures, no side effects ○ Cannabidiol ○ Diet ketogenic diet modified atkins low glycemic index limits amount of glutamate and GABA ○ surgery only about 30% of pts with focal seizures remove the area that is causing seizure  ○ neurostimulation vagus nerve stimulation responsive neurostimulation deep brain stimulation ○ first aid stay calm ease person to floor prevent injury (clear the area) do not restrain (loosen clothing) do not force anything into mouth TIME IT roll to side CALL 911: when seizure lasts more than 2 mins occurs in water person is pregnant, injured, or diabetic a second seizure starts consciousness fails to return in a few mins ○ lifestyle seizure triggers: sleep deprivation, interrupted sleep alcohol withdrawal long periods without food stress hyperventilation fever hormonal changes Anti-seizure drugs ○ Excitatory Glutamatergic synapse presynaptic targets VG NA channel blockers ○ MOA: cause depolarization (quiet down the system). overall decrease in glutamate into the synapse. ○ controls ALL ion channels (causes the side effects) ○ phenytoin (Dilantin) not basic. Not water soluble. Prodrug: fosphenytoin - enhances water solubility allowing for injectable form. block high frequency repetitive firing of action potentials PHENYTOIN IS SATURABLE MORE DRUG YOU HAVE, MORE EXPOSURE TO ADEs  INDICATION: focal seizures, generalized tonic-clonic, and status epilepticus METABOLISM: 2 aromatic groups, parahydroxylation, CYP2C9 and CYP2C19. Arene oxide intermediate. To HPPH. Can easily build up concentrations = toxicity. ADE: sedation, gingival hyperplasia, peripheral neuropathy, hirsutusm, TOXIC EPIDERMAL NECROLYSIS, rash to SJS, teratogenic!!, fetal hydantoin syndrome INHIBIT CYPS cimetidine, sulfonamindes INDUCE CYPs barbituates, ETOH phenytoin inducers CYP3A4, CYP2C19, CYP2D theophylline, oral contraceptives, steroids NO LONGER FIRST CHOICE ○ Carbamazepine (Tegretol) looks like phenytoin no ionizable groups - not very soluble. Can get through bilateral and bind on intracellular side INDICATION: temporal lobe epilepsy, focal, tonic-clonic ADE: dose related!, leukopenia (BBW), rash, SJS, teratogenicity (some) STRONG CYP3A4 INDUCER High risk of drug intx, warfarin, OC, steroids METABOLISM: affected by CYP3A4 inducers and inhibitors STRONG INDUCER OF CYP3A4 it is an auto-inducer. It induces its own metabolism. Peak after 4 weeks. metabolite: epoxide. More toxic than the carbamazepine HLAB1502 testing recommended ○ Oxcarbazepine (Trileptal) ketone group INDICATION: temporal lobe epilepsy, focal, tonic-clonic, atonic seizures METABOLISM: eliminated as glucuronide. Weak CYP3A4 inducer, less affected by CYP3A4 modulating drugs  ADE: less common, less severe. Dose related = ataxia, diplopia. Dose unrelated = rash, MORE HYPONATREMIA THAN CARBAMAZEPINE ○ Fosphenytoin (Cerebyx) prodrug of phenytoin hydroxymethyl group attached to phosphate designed for IV administration Used for status epilepticus and seizures occurring during neurosurgery more water soluble pro drug that cleaves into phenytoin and formaldehyde ○ VPA (Depakote, Depakene) alcohol Stimulates GABA synthesis INDICATION: absence seizures METABOLISM: glucuronide conjugation, omega - 1, hydroxyl group on alkyl chain ADE: lack of sedation, low ADV EFF profile. Hepatotoxicty rare but dose related. NOT SAFE IN PREGNANCY not highly protein bound minimal sedation! TREMORS IS A LONG TERM SIDE EFFECT. Increased by dose and time DDI: can displace phenytoin and inhibit metabolism of other ASD ○ lamotrigine (Lamictal) METABOLIZED: gluconoride. Steric - parahydroxy group. Electronics - 2 withdrawing groups that deactivate the ring. INDICATION: all seizure types, generalized seizures in childhood with absence attacks ADE: HA, NV, SJS DDI: hepatic inducers increase glucuronidation and clearance ○ topiramate (Topamax) looks like sugar monosaccharide derivative Na channel blocker as well as increases GABA at GABAa receptor also blockage of glutamate receptors metabolism: unchanged in urine. How stable is it in the stomach? Reasonably stable  INDICATIONS: focal seizures, generalized tonic-clonic, atonic, myoclonic ADR: sedation, cognitive slowing, confusion. FETAL MALFORMATIONS (cleft lip, palate) pretty messy drug DDI: CYP3450 metabolizes, carbamazepine, phenytoin increase topiramate metabolism ○ zonisamide (Zonegran) sulfonamide (not the antibiotic kind) MOA: VG NA channel blocker, blockage of T-type CA2 channels INDICATION: focal, myoclonic metabolized: CYP3A4 (partially). Parahydroxylation, but major metabolite is N-acetylation ADR: dizziness, ataxia, somnolence, insomnia, cognitive problems, rash (fatal) substrate of p450 DDI: phenytoin, carbamazepine (CYP3A4 inducers), VPA, cimitedine, erythromycin (CYP3A4 inhibitors) CI: patients with sulfonamide hypersensitivity ○ lacosamide (Vimoat) derivative of serine MOA: enhances slow inactivation of Na changes but does not completely block INDICATION: focal, tonic-clonic METABOLISM: metabolized by CYP2C19. Diapolation ADR: dizziness, HA, fatigue, ataxia, abnormal vision, diplopia, CARDIAC PROBLEMS, euphoria related (increased dopamine conc) low potential for DDIs Ca Channels (T type and L type) ○ gabapentin (neurontin) hit on top side (extracellular) VG Ca channel blocker GABAergic glutamate release (decreased) GABA release increase INDICATIONS: focal seizures hardly metabolized ADE: sedation, somnolence, dizziness, fatigue, nystagmus, ataxia  DDI: none based on PK PK: not lipophilic, not protein bound, excreted unchanged in urine ○ pregabalin (Lyrica) VG Ca channel blocker decreased glutamate release INDICATION: focal seizures hardly metabolized ADE: sedation, somnolence, dizziness, HA, weight gain, dry mouth, blurred vision pharmacology a little less complicated compared to gabapentin DDI: low potential ○ ethosuximide (Zarontin) MOA: VG Ca channel blocker structure related to phenytoin, except works on calcium channels INDICATION: ABSENCE SEIZURE (first line) PK: metabolized by CYP3A4 and 2E1 ADE: nausea, anorexia, mood changes, HA DDI: common (ethosuximide levels affected by co-medication) newer generation SV2A (synaptic vesicle protein) ○ levetiracetam (Keppra) ○ intraneuronal target on presynaptic side ○ present on glutamate and GABA synapse ○ MOA: binds to SV2A which alters release of GABA and Glu ○ INDICATION: focal, generalized tonic-clonic, myoclonic ○ PK: minimally metabolized ○ ADE: sedation, dizziness, asthenia ○ DOSE LOWERED IN RENAL INSUFFICIENCY AND ELDERLY ○ DDI: none, (amino acid derivative) postsynaptic target AMPA receptors ○ perampanel (Fycompa) MOA: AMPA-R blocker INDICATION: tonic-clonic PK: metabolized. By CYP3A4 highly protein bound ADE: dizziness, falls, drowsiness, fatigue, weight gain,  BBW: aggression, hostility, irritability, anger, homicidal ideation DDI: CYP3A4 inducers and inhibitors. Increased clearance of levonorgestrel ○ inhibitory Gabaergic synapse GABAa receptor modulator ion channel. Cl channel! GABAa receptor Barbiturates - lethal at about 10x hypnotic dose. Small therapeutic window. Have to have 2 substitutes in the 5 position. Optimal activity with 5-7 carbons needed because of lipophilicity, want the perfect lipophilicity to cross the BBB. ○ Barb likes it long ○ phenobarbital (Luminal) (active metabolite of primidone) GABAa receptor modulator (positive allosteric) INDICATIONS: focal, tonic/clonic PK: about half protein bound, renal excretion of non-metabolized drug. 100% bioavailable STRONG CYP2C and CYP3A4 INDUCER ADE: sedation - tolerance develops, nystagmus, ataxia, learning difficulties DDI: induces metabolism of other drugs (WARFARIN) ○ Primidone (Myosline) MOA: GABAa receptor modulator, depresses glutamate excitability, affects Na, K, Ca conductance INDICATIONS: focal, generalized tonic clonic essential tremors PK: metabolized by CYP2C19, strong cyp2c and xyp3a4 inducer similar ADE as phenobarbital primidone gets metabolized into phenobarbital benzos ○ Ben likes it more frequent ○ diazepam (Valium, Diastat) ○ lorazepam (Ativan) shortest half life ○ midazolam (Dormicum) ○ clonazepam (Klonopin) longest half life ○ GABAa receptor modulators ○ INDICATION: all seizure types including STATUS EPILEPTICUS  ○ ADV: tolerance (limits long term use), CNS depression, strong sedation, lethargy, aggressiveness, withdrawal, rebound effects ○ DDI: common - induction of CYPs - can cause DDIs ○ METABOLISM: ○ All these drugs are generally not very soluble ○ they are pretty lipophilic ○ they prefer an inactivated channel Anti-seizure Drug PK ○ Non-linear PK: kinetics resulting from saturable drug transfer, leading to variation of the kinetic parameter with drug conc perfect example: phenytoin drug concentration change either more or less than would be expected (in non-linear PK) can arise as a result of issues of capacity, binding, time, and blood flow nonlinear kinetics occur commonly at high concentrations following overdose, and in disease states need for assessing safety margin of a drug Non-linear drugs: phenytoin, diazepam, carbamazepine, VPA, gabapentin zonisamide (mixed) PK parameters for a drug change w change in dose dose dependent mixed order kinetics, saturated kinetics, capacity-limited kinetics doses not superimposable ○ Non-linear PK: Capacity limited Decrease bioavailability/curve in line GI transport: gabapentin why is this an issue? It’s hydrophilic. Metabolism: phenytoin SATURABLE DDI with cytochrome p450 enzymes lipophilic. Not excreting it in the first place arene oxide intermediate ○ Non-linear PK: time dependent metabolized more slowly, going to effect PK can result in toxicity ENZYME INDUCTION ○ Non-linear PK profile: Carbamazepine kinetics: time dependent carbamazepine mediates auto-induction!!! primarily metabolized by CYP3A4 it induces CYP3A4, CYP2C, and UGT  it induces its own metabolism, resulting in lower levels over time when the same dose is taken ○ Linear PK PK parameter do not change for change in dose dose independent zero or first order kinetics doses are superimposable ideally, we want it to be straight Epilepsy Therapeutics Typically do not start an anti-epileptic if just 1 seizure. ○ epilepsy: 2 unprovoked seizures within 24 hours Anti-seizure med: we are treating the seizures. Anti-epileptic drug: THERE IS ONLY ONE Selecting an ASM: ○ Is there a risk for repeated seizures? No: treat underlying condition Yes: Focal: carbamazepine, gabapentin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, perampanel, phenobarbital, phenytoin, pregabalin, topiramate, VPA, zonisamide Generalized (both hemispheres): ○ Tonic/clonic: carbamazepine, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, per a panel, phenobarbital, phenytoin, topiramate, VPA ○ Absence: ethosuximide, lamotrigine, VPA ○ Atonic/clonic: lamotrigine, oxcarbazepine, phenobarbital, phenytoin, VPA ○ Myoclonic: lamotrigine, levetiracetam, phenobarbital, topiramate, VPA, zonisamide General management ○ monotherapy is preferred ○ slow titrations improve tolerability ○ adjustments make on clinical response TDM can be helpful ○ if polytherapy required, select different MOA if possible TDM is helpful when ○ suspected toxicity ○ breakthrough seizures ○ adherence ○ suspected drug intx ○ if it is phenytoin ○ pregnancy ○ critical illness  TDM - we want to make sure timing is appropriate. Most labs are trough levels for ASDs. Only draw peak when they are toxic. Cross titrating ASMs ○ we want to reach goal dose of new ASM before we taper old ASM Side effect management ○ Peak: dose related. Can consider switching to ER formulation. Split dosing ○ New start or increased dose may need to slow titration ○ Morning vs. nighttime dosing ○ dose dependent may need reduction of first ASM and introduction of second ASM RASH ○ 3% of all ASMs ○ Biggest risk when multiple ASMs ○ Carbamazepine (risks) patients with HLAB1502 (testing recommended) patients with HLAA3101 ○ Lamotrigine (risks) high initial dose rapid dose increases co-administering with VPA Maculopapular (morbilliform) ○ begins 3-20 days after starting drug ○ itchy ○ resolves within weeks of stopping Urticaria (hives) ○ wheals with pale centers and red borders ○ migratory - change shape, size, location ○ anaphylaxis or angioedema may be associated erythema multiforme ○ targeted lesions ○ may involve mucous membranes ○ self-limiting SJS/TEN ○ 7-21 days after starting medication ○ sheet like skin and mucousal sloughing ○ less than 10% BSA - SJS ○ 10-30% BSA - SJS/TEN ○ Greater than 30% - TEN ○ mortality rate 10-30% Drug induced hypersensitivity syndrome (DIHS)/drug reaction with eosinophilia and systemic symptoms (DRESS) ○ 2-6 weeks after starting med  ○ fever, generalized rash, lymphadenopathy, facial edema, multiorgan failure ○ 10% mortality Rash treatment ○ If SJS, TENS, DIHS, DRESS discontinue immediately usually hospitalization with systemic corticosteroids Burn unit ○ non life threatening rash d/c quickly start a new ASM with rapid titration or load in hospital ○ use benzos to cover for breakthrough seizures if needed Bone health ○ osteopenia or osteoporosis in 38-60% of patients in clinics ○ increase risk of fractures ○ inhibits osteoblasts and/or activates osteoclasts ○ increased vitamin D metabolism ○ inhibition of calcium absorption ○ injury due to seizure Fractures and ASMs ○ increased risk with increased treatment duration ○ dose relationship with fractures ○ most associated: carbamazepine, clonazepam, phenobarbital, phenytoin, VPA ○ monitor vitamin D and BMD Treatments ○ Vitamin D supplementation 4000IU for adults 2000IU children ○ estrogen - may trigger seizures in some women Safety precautions in epilepsy ○ heavy machinery ○ heights ○ swimming/bathing ○ driving all states restrict for active seizures must be seizure free for 3-12 months ○ seizure first aid Suicidality ○ twice the risk of suicidal behavior/ideation ○ FDA requires BBW for all ASMs ○ no difference between drugs Sudden unexplained death in epilepsy patients (SUDEP) ○ Abrupt death in patients with epilepsy without apparent medical cause ○ 1 in 1000 in adults ○ risks  tonic-clonic frequency nocturnal seizures sleeping alone Issues in PWECP with epilepsy ○ progesterone - antiseizure ○ estrogen - proseizure ○ Catamenial epilepsy - ⅓ to ½ women ○ treatment: ASMs, benzos, acetazolamide, progesterone ○ menstrual cycle dysfunction - PCOS associated with VPA ○ decreased fertility more anovulatory cycles prolactin can decrease libido Contraception and ASMs ○ enzyme inducing AS can decrease effectiveness of oral contraceptives ○ IUD are safe from ASM DDI ○ In lamotrigine - decreases lamotrigine concentrations Pregnancy and post-partum ○ caution regarding pk changes during and after pregnancy everything is faster and increased, so drug levels will be decreased (serum) ○ breastfeeding is encouraged ○ Categories: A-D X: drug is contraindicated in pregnancy ○ fetal hydantoin syndrome ○ hemorrhagic disease of newborn ○ spina bifida ○ most are all category C ○ we prefer levetiracetam or lamotrigine teratogenicity risks ○ greater with poly therapy ○ greater with VPA ○ phenytoin, phenobarbital, topiramate ○ 5 or more seizures during pregnancy lowers verbal IQ pregnancy recommendations ○ seizure control ○ not advisable to change ASMs once pregnant (risk of seizures) ○ folic acid at least 1mg/day should be given to all women of childbearing potential ○ serum concentrations should be used to adjust dose Advanced age ○ Everything is slower ○ serum drug concentrations are increased ○ decreased protein binding  Highly protein bound: phenytoin, depakote, carbamazepine Goal number or seizures ○ Seizure free for at least 2 years ○ normal EEG ○ slow tapering Dementia Frontotemporal Dementia ○ frontotemporal (affects frontal and temporal lobes) ○ often miscategorized as psychiatric illness ○ between ages 45 and 65 ○ cerebral atrophy ○ tau deposits, pick bodies ○ SX: socially inappropriate behavior!!! “Criminal behavior” repetitive compulsive behavior poor judgement loss of empathy Abrupt mood changes memory loss speech difficulties movement or balance affected ○ No treatment available ○ patients need 24 hour care and monitoring ○ antidepressants often used to help with symptoms lewy body dementia ○ frontotemporal ○ cerebral atrophy ○ lewy bodies = abnormal deposits of a-synuclein in the brain ○ 1.5 million patients in US ○ deposits cause memory deficits and behavior changes ○ SX: visual hallucinations!!! delusions REM sleep disorder trouble initiating movement confusion hunched posture rigid muscles trouble balancing tremors ○ no treatment available ○ often diagnosed postmortem  alzheimer's disease ○ temporoparietal ○ 4th leading cause of death among elderly ○ 50% of people over 85 ○ cerebral atrophy ○ AB plaques, tangles ○ Normal aging vs. alzheimers normal: forgetting part of an experience, often able to remember later, able to use notes as reminder, able to care for oneself AD: forgetting whole experiences, rarely able to remember later, gradually unable to follow directions, use notes, or care for onself ○ Risk factors modifiable: HBP, HLD, obesity, diabetes, smoking, head trauma, environment, tobacco, alcohol non-modifiable: age older than 65, family he, female gender, genetics (5%) - chromosomes ○ SX: memory impairment, disrupted sleep patterns, personality changes, impaired movement, failure to recognize people, hallucinations, loss of language skills memory loss: slow and progressive onset anterograde amnesia followed by retrograde amnesia inability to learn and retain changes in behavior and personality loss of independence ○ FAST - functional assessment staging test (stages of disease progression) ○ pathology severe cortical shrinkage severe shrinkage of hippocampus enlarged ventricles disintegrating and defective microtubules Neurotoxicity, oxidative stress, and inflammation Loss of tau causes microtubule dissociation cholinergic hypothesis decreased number of synapses cholinergic transmission in basal forebrain decreased ACh levels biomarkers high CSF tau amyloid PET MRI ○ diagnosis cognitive tests, imaging techniques, labs ○ prognosis  progressive memory loss, patients live 4-8 years after diagnosis ○ treatment no cure only 2 categories of drugs available treating symptoms (stops working after 6-12 months) ○ ACHinterase inhibitors ○ NMDA antagonist ○ improve memory, functional status, behavioral sx, delay admission into more structured care (LTCF) Change disease progression (Serious ADE) ○ anti-AB immunotherapy ○ remove brain AB, reduce cognitive and functional decline Parkinson’s disease ○ midbrain ○ substantia nigra ○ lewy bodies ○ dementia Pathology (Dr Ryans slides only) ○ not all dementia is Alzheimer’s disease ○ vascular disease - vascular dementia (stroke) Medications that affect cognition ○ Alpha agonists ○ antiarrhythmics ○ anticholinergics ○ antiemetics ○ antihistamines ○ antipsychotics ○ antiseizures ○ Benzodiazepines ○ digoxin ○ diuretics ○ H2RA ○ narcotics ○ sedatives/hypnotics ○ skeletal muscle relaxants ○ steroids ○ TCAs anticholinergic medications ○ 1st gen antihistamines ○ TCAs ○ paroxetine ○ antipsychotics ○ urinary incontinence ○ parkinson's disease  ○ dry eyes, dry mouth, constipation, urinary retention, cognitive problems ○ cyclobenzaprine ○ DO NOT NEED TO KNOW HOW TO SCORE SOMEONE ON THE ANTICHOLINERGIC BURDEN TOOL Alzheimer's disease pathology summary ○ neurons shrink and die, particularly cholinergic neurons ○ reduce ACH = more cognitive problems ACH promotes neurotransmisson ○ glutamate receptors are over-activated leading to neurotoxicity ○ Beta-amyloid plaques form which are neurotoxic **hallmark of dementia** ○ Tau proteins form tangles blocking neuron transport system ○ brain becomes inflamed Hallmarks of dementia: Apolipoprotein E ○ 25% if you have 2 parents with a recessive gene ○ more copies = more likely to get Alzheimer’s ○ APOE e4 Activities of daily living (ADLs) ○ walking ○ bathing ○ dressing ○ toileting ○ brushing teeth ○ eating Instrumental activities of daily living (IADLs) ○ cooking ○ driving ○ using phone ○ shopping ○ keeping track of finances ○ managing medication ○ usually first to go Onset of dementia ○ late onset: mid 60s most common may involve APOE e4 ○ early onset 30-60s very rare usually caused by gene changes passed down from parent to child Acetylcholinesterase Inhibitors ○ increases the amount of ACH. Acts oppositely of anticholinergics ○ does NOT affect progression of AD  ○ MOA: inhibits centrally active acetylcholinesterase, which is responsible for the breakdown of ACH, resulting in an increase of ACH available for synaptic transmission. ○ SLUDGE: salivation, lacrimation, urination, defecation, GI distress, vomiting ○ PRECAUTIONS: rhabdomyolysis, PUD, respiratory disease, ○ DDI: anticholinergics, antipsychotics, BBs, cholinergic agents, corticosteroids, neuromuscular blockers ○ ADE: ND, insomnia, bradycardia ○ MONITOR: mental status, weight, GI tolerability ○ Donepezil (Aricept) start low then increase MOA: reversible acetylcholinesterase inhibitor ADE: bradycardia, heart block, GI symptoms, muscle cramps, anorexia DDI: NSAIDs - increased intestinal bleeding maximize dose as tolerated. We want them to be on at least 10mg! 5, 10, 23mg tablets and patches used a lot for other forms of dementia Mild, moderate, severe AD ○ Rivastigmine (Excelon) Available in caps and patches helps with adherence and GI effects (patch) mild to moderate AD MOA: reversible acetylcholinesterase inhibitor same ADE DDI: metoclopramide, beta blockers ○ galantamine (Razadyne) has oral solution useful when pt has trouble swallowing mild to moderate AD, vascular dementia MOA: reversible acetylcholinesterase inhibitor Same ADE DDI: albuterol, aspirin, amlodipine ○ Benzgalantamine (Zunveyl) designed to reduce GI effects prodrug for galantamine available 2025 NMDA receptor antagonist ○ Memantine (Nameda) caps, tabs, solution Moderate to Sever AD!!! MOA: NMDA receptor antagonist. Blocks toxic effects associated with excess glutamate ADE: dizziness, HA, constipation, confusion DDI: nicotine, ranitidine, cimetidine  ○ PRECAUTIONS: CVD, hepatic/renal dosing, seizure disorders, alkaline urine decreases clearance ○ DDI: carbonic anhydrase inhibitors, sodium bicarbonate, trimethoprim ○ ADE: CNS effects ○ monitoring: mental status ○ generally is an add on, but can be used as monotherapy ○ Combination therapy: Memantine XR/donepezil (Namzaric) for moderate to severe Alzheimer’s dementia Anti-amyloid monoclonal antibodies ○ very effective at getting rid of plaques. We want to start this EARLY!! If the brain is covered in plaques, if we try to take them off, it is going to cause a ton of inflammation. ○ MOA: not clearly defined. Anti-amyloid antibodies are given by infusion. Antibodies clear amyloid from the body and brain. ○ This is now looking at first line therapy over others. Next, would be acetylcholinesterase inhibitors memantine is an add on for moderate to severe ○ PRECAUTIONS: appropriate use ○ DDI: efgartigimod alpha. Rozanolixizumab ○ ADE: amyloid related imaging abnormalities (ARIA), diarrhea, confusion, infusion rxns (pre-medicate) ○ MONITOR: confirm beta amyloid pathology through PET scan or spinal tap, brain MRI prior to infusions, MRI changes, ARIA, mental status ○ AMYLOID RELATED IMAGING ABNORMALITIES mostly asymptomatic but also cognitive decline, HA, seizure, fall risk factors medication dose high, APOE talus, pre-treatment micro hemorrhage TX: corticosteroids, may stop treatment ○ Aducanumab ( Aduhelm) IV solution MOA: reduces amyloid brain levels efficacy? INDICATION: mild cognitive impairment, mild AD dementia ADE: ARIA-E: brain edema ARIA-H: micro hemorrhage, bleeding BBB leakage HA confusion, delirium FDA approval only approved for medicare ○ Lecanemab (Leqembi) IV  Most used INDICATION: mild cognitive impairment, AD with mild dementia same ADE Boxed warnings APOE E4 testing recommended prior to initiations MRI required increased risk of bleeding if pt is on anticoagulant or thrombocytes agents slightly more safe ○ Donanemab (Kisunla) IV MRI required may need to premedicate for infusions boxed warning: APOE E4 testing recommended increased risk of bleeding very expensive Can stop therapy if plaques are gone Realistic therapy expectations ○ slow decline ○ delayed long term care placement ○ expected decline without treatment (MMSE decline of 2-4 pts per year Discontinuation of pharmacotherapy ○ patient/family decide to stop ○ intolerable adverse effects ○ comorbidities make use risky or futile ○ rate of decline greater on tx than before ○ dementia progressed to no benefit ○ patient non adherent ○ TAPER BEFORE STOP ○ monitor over 1-3 months for evidence of decline Non-cognitive symptoms of dementia ○ agitation/combative ○ sleep disturbances ○ wandering ○ depression ○ seizures ○ anxiety ○ psychosis (sun downing) Pharmacological therapy for non-cognitive symptoms ○ generally go low and slow and document ○ risk versus benefit ○ atypical antipsychotics for psychosis and agitation BBW: increased risk of mortality in dementia related psychosis ○ sleep aids avoid hypnotics, benzos, and antihistamines if possible  really just melatonin ○ Antiseizure drugs monitor for sedation and increased confusion ○ antidepressants avoid anticholinergics (paroxetine, TCAs) Comorbidities in dementia ○ very common in geriatric patients ○ HTN, depression, epilepsy, pain, stroke, UTIs Nonpharmacologic approaches to dementia ○ cognitive stimulation ○ social interactions ○ healthy diet ○ adequate sleep ○ proper personal hygiene ○ physical exercise ○ safety inside and outside home ○ long term planning for health ○ medical POA or normal POA (better done early) ○ effective communication Caring for dementia patients ○ speak slow and clear using short sentences ○ make eye contact ○ give them time to respond ○ give them simple choices ○ tone should be positive and friendly ○ acknowledging what they say adherence and dementia ○ memory aids for pill planners ○ reduce pill burden (polypharmacy is an issue) ○ reduce timing of medications if possible Alzheimer’s disease prevention ○ good quality education ○ get hearing aids when you need them ○ treat depression effectively ○ Head protection ○ reduce smoking ○ prevent/reduce HTN ○ maintain healthy weight ○ treat high LDL ○ treat vision loss ○ reduce air pollution exposure Severity of dementia and treatment ○ MoCA - Montreal cognitive assessment ○ severity of dementia determined by clinical testing and neuropsychiatric evaluation ○ MoCA requires about 10 minutes to administer and is useful in early detection ○ range 0-30 (follow up if less than 24) 18-25: mild cognitive impairment 10-17: moderate cognitive impairment less than 10: severe cognitive impairment